bims-unfpre 2025-11-02 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–11–02
ten papers selected by
Susan Logue, University of Manitoba

Inhibition of Histone Deacetylases Induces Cancer Cell Apoptosis Through the PERK Pathway of ER Stress Response.
Targeting ER stress-mediated apoptosis by MSC-derived exosomes: A novel therapeutic strategy against pulmonary fibrosis.
Activation of IRE1 Endonuclease Activity Regulates Zika Virus Replication and Antiviral Response During Infection in Human Microglia.
Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review).
Role of Unfolded Protein Response in the Apoptosis Induced by Alphaarterivirus: IRE1α as an Essential Pathway for In Vitro Replication.
The Role of C/EBP-Homologous Protein in Idiopathic Inflammatory Myopathies.
Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy.
Cucurbitacin B suppresses glioblastoma via the STAT3/ROS/endoplasmic reticulum stress pathway.
DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.
Tauroursodeoxycholic acid-induced increase in ectopic muscle mineralization occurs exclusively in dystrophic muscles and is independent of endoplasmic reticulum stress.

J Cell Mol Med. 2025 Nov;29(21): e70928

Inhibition of Histone Deacetylases Induces Cancer Cell Apoptosis Through the PERK Pathway of ER Stress Response.

Xuan Wang, Caiyun Yang, Yili Yang, Feng Xu, Donglan Yuan, Yuexi Gu.

  Activation of the endoplasmic reticulum (ER) stress is an adaptive response to disturbed ER homeostasis caused by the accumulation of misfolded or unfolded proteins, or an acute increase in the entry of newly synthesised or mutated proteins into the ER lumen. Overwhelmed or prolonged ER stress causes apoptotic cell death or a maladaptive state of the cell, resulting in various pathological diseases including cancer, inflammation and aging. With a screening of a chemical compound library, here we show that inhibition of histone deacetylases (HDACs) induces ER stress, along with increased retro-translocation of misfolded proteins from the ER lumen to the cytosol for proteasomal degradation. HDAC inhibitors (HDACi) activate the PERK-eIF2α subbranch of the unfolded protein response (UPR), whereas the IRE1α and ATF6 pathways are not affected. Inhibition of the PERK subbranch with specific siRNA or a small molecule inhibitor ameliorates HDACi-induced apoptotic cell death. In addition, a non-phosphorylatable mutant of eIF2α, a critical substrate that transduces the PERK-mediated ER stress response, abolishes apoptosis induced by HDACi, but not by the DNA damage reagent doxorubicin. HDACi reduce the sizes of tumours formed from wildtype but not eIF2αS51A-mutant cells in a xenograft model, further demonstrating the involvement of the PERK subbranch in HDACi-induced ER stress and cell death. Our study reveals novel effects of the well-studied family of HDAC inhibitors, which can be explored further in clinics to treat certain types of cancer manifested with abnormal ER stress conditions.

Keywords:  ER stress; HDAC inhibitors; PERK pathway; apoptosis; quisinostat; unfolded protein response

DOI:  https://doi.org/10.1111/jcmm.70928
Regen Ther. 2025 Dec;30 933-945

Targeting ER stress-mediated apoptosis by MSC-derived exosomes: A novel therapeutic strategy against pulmonary fibrosis.

Ruixi Luo, Yaqiong Wei, La Wang, Peng Chen, Didong Lou, Weiyi Tian.

   Introduction: Idiopathic pulmonary fibrosis (IPF) is marked by a gradual decline in pulmonary function over time and is associated with a grim prognosis. In the pathogenesis of IPF, persistent endoplasmic reticulum (ER) stress plays a significant role in promoting fibrosis through pathways involving apoptosis. Mesenchymal stem cell-derived exosomes (MSC-Ex) have shown promise in mitigating pulmonary fibrosis by inhibiting apoptosis. Nonetheless, the precise mechanisms underlying this effect remain unclear. In our previous findings, we demonstrated that MSCs alleviate pulmonary fibrosis by regulating ER stress. Building upon this, we sought to investigate whether MSC-Ex could mitigate alveolar epithelial cell apoptosis through the ER stress pathway. We posited that targeting ER stress could represent a crucial mechanism by which MSC-Ex alleviate apoptosis in IPF models.
Methods and results: In this study, bleomycin (BLM) induced apoptosis in A549 cells, and MSC-Ex treatment reduced apoptotic cells and the Bax/Bcl-2 ratio. ER stress is involved in BLM-induced apoptosis in A549 cells, and MSC-Ex reduced ER stress-related protein (Bip and CHOP) expression and reversed the morphological changes of the ER in A549 cells. Moreover, blockade of ER stress with ER stress inhibitor TUDCA contributed to the amelioration of apoptosis in A549 cells, indicating that MSC-Ex reduced BLM-induced apoptosis at least partly by modulating ER stress. In vivo, MSC-Ex injection decreased BLM-induced pulmonary fibrosis in mice, as well as ER stress and apoptosis in the lung tissues.
Conclusions: In conclusion, ER stress induced apoptosis in BLM-treated A549 cells, and MSC-Ex treatment mitigated apoptosis via inhibiting ER stress. This study provides a novel mechanism for MSC-Ex-mediated protection on apoptosis in an IPF model and suggests that MSC-Ex could be a promising therapeutic strategy for IPF.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Exosome; Mesenchymal stem cell; Pulmonary fibrosis

DOI:  https://doi.org/10.1016/j.reth.2025.10.004
Viruses. 2025 Sep 24. pii: 1291. [Epub ahead of print]17(10):

Activation of IRE1 Endonuclease Activity Regulates Zika Virus Replication and Antiviral Response During Infection in Human Microglia.

Tomás Hernández-Díaz, Aarón Oyarzún-Arrau, Aracelly Gaete-Argel, Delia López-Palma, Javier López-Schettini, Dominique Fernández, Fernando Valiente-Echeverría, Fabiola Osorio, Ricardo Soto-Rifo.

  Zika virus (ZIKV) can infect and replicate in the endoplasmic reticulum (ER) of different human cell types, including neural progenitor cells, radial glial cells, astrocytes, and microglia in the brain. ZIKV infection of microglia is expected to trigger both ER stress and the induction of an antiviral response through production of type-I interferons and pro-inflammatory cytokines, contributing to neuroinflammation during infection. Despite their critical role in ZIKV pathogenesis, the interplay between ER stress and the antiviral response during infection has not been fully characterized in human microglia. In this work, we show that infection of a human microglia cell line with ZIKV triggers the induction of an antiviral response and the activation of the endonuclease activity of the unfolded protein response sensor IRE1. Interestingly, we observed that both IRE1 and XBP1 were sequestered to the viral replication sites during infection. Moreover, pharmacological inhibition or hyperactivation of the endonuclease activity of IRE1 resulted in reduced viral titers. As such, while inhibition of IRE1 resulted in an increased type-I interferon response, hyperactivation led to a decrease in ZIKV RNA levels and the appearance of ER-derived cytoplasmic structures containing NS3, IRE1, and XBP1. Together, our data indicate that regulation of the endonuclease activity of IRE1 is critical for both ZIKV replication and immune activation, highlighting the potential of the ER stress sensor as a target for the development of antivirals to treat ZIKV infections.

Keywords:  ER stress; IRE1; Zika virus; innate immune response; microglia

DOI:  https://doi.org/10.3390/v17101291
Mol Med Rep. 2026 Jan;pii: 18. [Epub ahead of print]33(1):

Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review).

Zhiwei Yuan, Zheng Xia, Liyun Ling, Jingzhe Xie, Feng Zhang.

  Mucin 2 (MUC2) is the primary structural component of the intestinal mucus layer and is essential for maintaining the integrity of the mucus barrier and influencing the development of inflammatory bowel disease (IBD). Disruption of MUC2 production or secretion compromises barrier function, increasing susceptibility to the chronic mucosal inflammation characteristic of IBD. Given their large size and complex folding requirements, immature MUC2 precursors easily accumulate in the endoplasmic reticulum (ER) and cause ER stress, leading to activation of the unfolded protein response (UPR). The UPR restores ER homeostasis by reducing protein synthesis, enhancing folding, and degrading misfolded proteins. The mammalian UPR has three known signaling branches: Pancreatic ER kinase, ER transmembrane inositol‑requiring enzymes 1α and β (IRE1α and IRE1β) and activating transcription factor 6. Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the ER. Importantly, IRE1β‑AGR2 signaling potentially serves as a superior regulatory mechanism for controlling UPR activation caused by the misfolding of MUC2 in goblet cells. The present review highlights the critical role of MUC2 dysfunction and UPR imbalance in IBD pathogenesis. Targeting the association between novel UPR signaling pathways and restoring MUC2 protein function may provide new insights into IBD research and treatment.

Keywords:  anterior gradient 2; inflammatory bowel disease; inositol‑requiring enzymes 1β; mucin 2; unfolded protein response

DOI:  https://doi.org/10.3892/mmr.2025.13728
Viruses. 2025 Sep 25. pii: 1301. [Epub ahead of print]17(10):

Role of Unfolded Protein Response in the Apoptosis Induced by Alphaarterivirus: IRE1α as an Essential Pathway for In Vitro Replication.

Santiago Emanuel Colina, Macarena Marta Williman, María Soledad Serena, María Gabriela Echeverría, Germán Ernesto Metz.

  The perturbation of ER homeostasis by viral infection gives rise to the unfolded protein response (UPR), characterized by the activation of three signaling pathways. PERK, IRE1, and ATF6 have been identified as the primary mediators responsible for restoring homeostasis or leading to apoptosis in response to stress. Alphaarterivirus equid, known as equine arteritis virus (EAV), is a RNA virus with importance in the equine industry that could persist in semen and lead to abortions in pregnant mares. The present article explores the consequences of in vitro infection with the EAV Bucyrus strain on UPR. Employing RT-PCR, qPCR and Western blot, our investigation has revealed the activation of PERK and IRE1α pathways, whilst ATF6 has been suppressed. Furthermore, the p38α MAPK, caspase-12, and CHOP genes were found to be upregulated, demonstrating the induction of apoptosis. Finally, in the inhibition experiments, the PERK pathway was found to be implicated in the modulation of viral replication in the initial phases of infection. Conversely, the IRE1α pathway was identified as the predominant UPR pathway in EAV replication, as evidenced by the complete inhibition of replication observed in these experiments. Consequently, the further exploration of this UPR pathway is necessary to determine whether it can effectively suppress EAV replication.

Keywords:  ER stress; IRE1α; PERK; RNA virus; apoptosis; equine arteritis virus

DOI:  https://doi.org/10.3390/v17101301
J Cell Mol Med. 2025 Nov;29(21): e70919

The Role of C/EBP-Homologous Protein in Idiopathic Inflammatory Myopathies.

Monica Sciacco, Patrizia Ciscato, Letizia Bertolasi, Maria Guttuso, Stefania Corti, Deborah Mattinzoli, Masami Ikeata, Giuseppe Castellano, Giacomo Pietro Comi, Simona Zanotti.

  The Idiopathic Inflammatory Myopathies (IIMs) are a group of autoimmune disorders characterised by persistent muscle inflammation and diverse clinical manifestations. Common symptoms include muscle weakness, myalgia, and elevated serum creatine kinase levels. Recent findings highlight the relevance of muscle fibre necrosis in IIMs. We therefore grouped our IIM patients according to the percentage of necrotic fibres in muscle biopsy. Our clustered patients were analysed for the inflammatory milieu, the capillary network, and the endoplasmic reticulum stress. In patients with a higher percentage of necrotic fibres we detected a more marked presence of CD206 positive cells, an activation of the endothelial-mesenchymal transition process, an altered capillary network, more marked ER stress and connective tissue deposition. Furthermore, our study revealed a key role of C/EBP-homologous protein (CHOP), a multifunctional transcription factor that contributes to cellular functions including apoptosis, autophagy, inflammation, mediation of ER stress and induction of fibrosis. Our study suggests that CD206 positive cells and CHOP have an important role in pathogenetic mechanisms and could therefore be considered possible therapeutic targets to modulate the inflammatory response of these patients, namely to contain or slow down the progression of fibrosis.

Keywords:  CD206; CHOP; ER stress; EndoMT; inflammatory myopathy; necrosis

DOI:  https://doi.org/10.1111/jcmm.70919
Sci Transl Med. 2025 Oct 29. 17(822): eady5288

Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy.

Miriam M Fonseca, Oriana Gelblung, Sarah D Pennypacker, Taylor Brooks, Michael Limia, James W Morgan, Xuewei Zhu, Luis C Tovias-Sanchez, Alejandro Pluma-Pluma, Ruth Elena Martinez, Mathew R Eber, Sun H Park, Cristina M Furdui, Deepika Awasthi, Alexander Emmanuelli, Byuri A Cho, Chen Tan, David I Shalowitz, Samuel S Lentz, Michael Kelly, Anderson O'Brien Cox, Lindsay Macnamara, Fang-Chi Hsu, Yusuke Shiozawa, Wesley Hsu, Takao Iwawaki, Lance D Miller, Glenn J Lesser, Roy Strowd, Juan R Cubillos-Ruiz, E Alfonso Romero-Sandoval.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in patients with cancer. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion-resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced the overproduction of mitochondria-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages toward an inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglion neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer were associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in patients with cancer who are receiving paclitaxel.

DOI: https://doi.org/10.1126/scitranslmed.ady5288
Sci Rep. 2025 Oct 27. 15(1): 37485

Cucurbitacin B suppresses glioblastoma via the STAT3/ROS/endoplasmic reticulum stress pathway.

Guangyao Lv, Shanshan Sun, Xueying Li, Ruxia Han, Shule Liu, Mei Lu, Xinfu Gao, Jianqiao Zhang, Wenwen Lv.

  Cucurbitacin B (CuB), the tetracyclic triterpenoid compound belonging to cucurbitaceae family, demonstrates significant anticancer properties across various tumor types. However, its efficacy against glioblastoma (GBM), particularly in overcoming blood-brain barrier (BBB) and unique tumor microenvironment, remains a critical area of investigation. Our study reveals that CuB causes GBM cell apoptosis via STAT3/ROS/endoplasmic reticulum (ER) stress pathway. To enhance targeted delivery, we developed M@CuB-Lips, a novel formulation of CuB encapsulated in cancer cell membrane-coated liposomes. In vitro and in vivo experimental results verified targeted M@CuB-Lips delivery to brain tumor sites, demonstrating significant tumor inhibition and enhanced effector T-cell infiltration. These findings underscore CuB's potential in GBM therapy, particularly through STAT3 suppression and ROS-ER Stress pathway activation, while M@CuB-Lips offers a promising strategy for targeted drug delivery.

Keywords:  Cucurbitacin b; Endoplasmic reticulum stress; Glioblastoma; Liposome; Target therapy

DOI:  https://doi.org/10.1038/s41598-025-21526-0
Cell Rep. 2025 Oct 28. pii: S2211-1247(25)01264-1. [Epub ahead of print]44(11): 116493

DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.

Abd-El Monsif A Shawky, Allison V Eckhardt, Josef B Mick, Mahmoud F Dondeti, Kenneth Avanzino, Constantine A Simintiras, Maria Hatzoglou, Anastasios Vourekas.

  Regulation of eukaryotic mRNA translation initiation greatly impacts gene expression and is critical for cellular stress response. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in scanning and translation regulation in non-stressed and stressed cells remains incompletely understood. Here, we show that DDX3X associates with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex and exerts dual regulatory effects, promoting or repressing translation of select mRNAs under basal conditions and reversing this regulation during acute endoplasmic reticulum stress. Initiation profiling reveals mechanistically distinct modes of DDX3X action linked to its binding patterns across the 5' UTR and coding sequence. We further uncover that mRNAs selectively regulated by DDX3X exhibit specific patterns of cytidine N4-acetylation near start codons, with shared de-repression observed upon NAT10 knockdown. Together, our findings reveal DDX3X as a context-sensitive regulator that has a possible functional connection with epitranscriptomic features in translation control.

Keywords:  CP: Molecular biology; DDX3X; RNA helicase; ac4C; eIF3; endoplasmic reticulum stress; post-transcriptional modifications; post-transcriptional regulation of gene expression; translation initiation

DOI:  https://doi.org/10.1016/j.celrep.2025.116493
Sci Rep. 2025 Oct 28. 15(1): 37704

Tauroursodeoxycholic acid-induced increase in ectopic muscle mineralization occurs exclusively in dystrophic muscles and is independent of endoplasmic reticulum stress.

Justyna Róg, Dorota Dymkowska, Bernadeta Michalska, Olga Krupska, Krzysztof Milewski, Paweł Matryba, Artur Wolny, Monika Pawłowska, Łukasz Bożycki, Dawid Stępnik, Dariusz C Górecki, Krzysztof Zabłocki.

Calcification of dystrophic skeletal muscles was described previously and attributed, among others, to ER-stress, elevated phosphate concentration and chronic inflammation. Tauroursodeoxycholic acid (TUDCA) is considered an artificial chaperone protecting cells against ER-stress thus could prevent an ectopic mineralisation of soft tissues. Because an enhanced ER-stress is a feature of dystrophic muscles and it promotes soft tissue mineralisation we hypothesised that TUDCA treatment should reduce mineral deposits in dystrophic skeletal muscles, and tested this concept using two mouse models of DMD. Four-week old mdx, mdxβetageo and w/t mice were administered TUDCA in drinking water for 4 weeks. At 8 weeks, following tissue-clearing and calcium minerals staining with alizarin, mineralisation was evaluated using whole body scanning. Additionally, isolated skeletal muscles were analysed by Western blotting for ER-stress and calcification markers, and using various microscopic methods. Enzymatic activity of alkaline phosphatase was also assayed. Unexpectedly, TUDCA enhanced calcification of dystrophic but not dystrophin-positive muscles. TUDCA did not affect the elevated ER-stress markers found in dystrophic muscles nor impact pro-calcifying proteins RUNX2, Osterix and BMP2/4, which were also overexpressed in dystrophic muscles. The alkaline phosphatase levels, which were reduced in dystrophic muscles, were not affected by this treatment. The increase in ectopic calcification in dystrophic muscles induced by TUDCA is specific to muscles lacking dystrophin. This effect is not linked to the alleviation of ER stress or the overexpression of proteins directly involved in calcium mineral accumulation.

DOI: https://doi.org/10.1038/s41598-025-21534-0